PDE10A is of the known 12 families of phosphodiesterases, the one with the most restricted expression, largely confined to the brain. It is a dual specificity enzyme with both cAMP and cGMP as substrates. As such, PDE10A inhibition increases the levels of both these second messengers and therefore augments receptors and signaling positively coupled to either PKA or PKG. The functional consequences of such inhibition are dependent on both the expression pattern or localization of the enzyme, as well as the activity of the relevant network of neurons. As PDE10A expression is most highly expressed in the caudate and putamen (also referred to as the striatum in lower species), the emphasis of the vast majority of investigators has been on the effect of PDE10A inhibition in disorders with altered caudate/putamen function, specifically schizophrenia and Huntington's Disease (HD). The enzyme is however more widely expressed, including cortex, hippocampus, prefrontal cortex and outside the CNS, the testis.
Developmental syndromes range in severity and include disorders such as Prader-Willi syndrome, 16p11.2 deletion syndrome, 16p11.2 recurrent microdeletion, Albright hereditary osteodystrophy, Alstrom syndrome, Bardet-Biedl syndrome, Borjeson-Forssman-Lehmann syndrome, Cohen syndrome, fragile X syndrome, fragile X syndrome (Prader-Willi Subtype), Down syndrome, Klinefelter syndrome, Turner syndrome, Smith-Magenis syndrome, Angelman syndrome, 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia, 2q37 Microdeletion syndrome, 3q29 Recurrent Deletion, Achondroplasia, ADNP-Related Intellectual Disability and Autism Spectrum Disorder and melanocortin 4 receptor (MC4R) deficiency. For example, Prader-Willi syndrome (PWS) is a genetic disease caused by lack of expression of genes from an imprinted region of the paternally inherited chromosome 15q11-q13, near the centromere (Aycan and Bas, J Clin Res Pediatr Endocrinol, 6(2):62-67 (2014)). The frequency of the disease is between about 1/10,000 and 1/30,000 with approximately 400,000 PWS patients living worldwide. PWS is a spectrum disorder which affects many systems in the body. Subjects with PWS typically suffer from a host of symptoms including neurologic, cognitive, endocrine, and behavioral abnormalities. Initially, infants exhibit hypotonia (floppy baby syndrome) and experience difficulty in sucking and feeding which can lead to growth delay. Subjects with PWS frequently have poor muscle tone, growth hormone deficiency, low levels of sex hormones, a constant feeling of hunger and excessive appetite (hyperphagia). They overeat, leading to weight gain, obesity and a high incidence of diabetes. Other signs appear including short stature, poor motor skills, underdeveloped sex organs, and mild intellectual and learning disabilities. PWS subjects may experience delayed speech and language development, and infertility. Behavioral symptoms may include cognitive impairment, cognitive rigidity, emotional lability and obsessive-compulsive behavior, with autistic symptomology, psychotic episodes, and biopolar disorder with psychosis. Additional clinical manifestations may include excessive daytime sleepiness, scoliosis, osteopenia/osteoporosis, decreased gastrointestinal motility, sleep disturbances, and reduced pain sensitivity.
There remains a need for methods for treating developmental syndromes.